HIV/AIDS News

NIH Scientists Highlight Role of Macrophages in HIV Infection

Date: January 1, 2001Source: National Institutes of Health (NIH)Author: National Institute of Allergy and Infectious Diseases (NIAID)URL: http://www.nih.gov/news/pr/jan2001/niaid-01.htm

Researchers have known for years that HIV can infect specialized immune system
cells called macrophages, but new research suggests these cells may play a
larger role in HIV infection than previously believed. In the current online
early edition of Proceedings of the National Academy of Sciences, scientists
from the National Institute of Allergy and Infectious Diseases (NIAID) report
that macrophages contain and continue to produce large amounts of an HIV-like
virus in monkeys even after the virus depletes CD4+ T cells, the primary HIV
target in infected individuals. This discovery provides new insight on how the
virus might survive in the midst of antiretroviral drugs and suggests new
strategies for eliminating the virus from the body."Our research suggests that macrophages are an underappreciated reservoir of
virus in HIV infection," says study author Malcolm A. Martin, M.D., chief of
NIAID's Laboratory of Molecular Microbiology. "These cells become infected
immediately after exposure to HIV, are relatively resistant to virus killing,
and are able to produce lots of new virus. Most currently available treatments
target HIV during its infection of T cells, but if the virus also infects and
accumulates in large amounts in macrophages, additional drugs may be
required."Highly active antiretroviral therapy, or HAART, can reduce HIV to undetectable
levels in a person's blood, but the virus usually bounces back when the drugs
are stopped. Because HIV enters and destroys CD4+ T cells early in infection,
many researchers believe those cells are the most likely source of the
rebounding virus. Several studies have questioned that idea, however, leaving
scientists uncertain of the key reservoir for latent HIV. Dr. Martin and
colleagues studied SHIV, a specially designed hybrid virus in monkeys, to see
if macrophages might be a major virus source.SHIV strains do not exist in nature but can be generated in the laboratory by
combining the outer envelope proteins of HIV with a core of simian
immunodeficiency virus (SIV), a closely related monkey retrovirus that also
induces AIDS in inoculated animals. SHIV infection in monkeys is an extremely
rapid and exaggerated model of HIV infection in humans that allows scientists
to address certain clinical aspects of retrovirus biology that are difficult
or impossible to study in people. "SHIV viruses rapidly deplete CD4+ T cells
yet continue to grow to very high levels in the animal, allowing us to look at
where else the virus might be hiding," explains Dr. Martin. "Our studies would
be impossible to do in people because natural HIV infection does not deplete
T-cell populations as quickly or as completely."Dr. Martin and his colleagues infected macaques with a highly virulent SHIV
strain and watched the virus as it infected cells. SHIV rapidly entered the
animals' CD4+T cells and quickly eliminated most of those cells from the
blood, lymph nodes and other tissues. The infected monkeys continued to
produce high levels of virus, however, suggesting that SHIV also had infected
another cell type. When the researchers examined lymphoid organs such as lymph
nodes and spleen for the source of the remaining virus, they found that 95
percent of the virus-producing cells were macrophages and only 1 to 2 percent
were T cells.Anthony S. Fauci, M.D., director of NIAID, says this might partially explain
the results of studies conducted recently by his laboratory and others. "When
patients on HAART stop their therapy, the virus that bounces back usually
differs from the latent virus in their CD4+ T cells, suggesting another
reservoir for HIV. If the SHIV model is giving us a glimpse of what is
happening with HIV in humans, it might point to macrophages as an important
reservoir of HIV in humans receiving HAART."Dr. Martin believes this information might change how physicians treat HIV
infections. Currently available drugs designed to attack the virus in T cells
do not eliminate all of the virus in the body, particularly those in
macrophages. The researchers tested this idea by checking whether a potent
reverse transcriptase (RT) inhibitor could control both the early T-cell and
late macrophage stages of the SHIV infection. RT inhibitors are antiretroviral
drugs and key components of HAART. The team first treated macaques early in
the infection, when SHIV was predominant in CD4+T cells. In this group of
animals, the drug readily and efficiently reduced virus levels and protected
the monkeys from any T-cell loss. However, when the RT inhibitor was given
only during the later macrophage phase of infection, the drug had no effect."If we want to completely eliminate the virus, we need to attack it everywhere
it lives, not just in the T cells," says Dr. Martin. "Our studies suggest we
need new classes of antiretroviral agents that can target HIV during
infections of tissue macrophages. They potentially could eliminate this
reservoir of virus and obviously complement currently available drugs."The researchers plan to use the SHIV model to further investigate the role of
macrophages in HIV infections. SHIV infection in monkeys provides an ideal
opportunity to study infected macrophages in a living animal, a better
alternative than the tissue culture experiments scientists have used to date.
Studies are under way to see how macrophages respond to SHIV infection and how
long these infected cells can survive. The researchers also will test
additional drugs, which they hope eventually will include new candidate
antiretroviral compounds designed to stop latent virus from rebounding.NIAID is a component of the National Institutes of Health (NIH). NIAID
supports basic and applied research to prevent, diagnose, and treat infectious
and immune-mediated illnesses, including HIV/AIDS and other sexually
transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.A copy of this article is available online at www.pnas.org/papbyrecent.shtml.Press releases, fact sheets and other NIAID-related materials are available on
the NIAID Web site at www.niaid.nih.gov.